The long-term goal of this study is to elucidate the mechanism(s) responsible for the decline in skeletal muscle performance with age. Age- related decreases in skeletal muscle mass, strength and quality, are termed sarcopenia and may contribute to physical disability and loss of independence. In addition to decreased mass, decreases in muscle contractile force have been reported in several mammalian species with age including humans. Despite the importance of muscle mass and strength in preventing disability, the biological mechanisms responsible for these phenomena are poorly understood. Although a large volume of literature demonstrates that muscle strength declines with aging, a central issue remains unresolved. Does muscle atrophy alone account for the decreased contractile force with age? We have proposed that alterations in intracellular calcium activation are an important component of the differences in muscle strength between adult and aged muscles. Currently, there is only limited information available on the regulation of intracellular calcium levels in skeletal muscle of aged animals. The purpose of this proposal is to determine mechanisms responsible for the decline in skeletal muscle contractility with aging. The molecule that transduces sarcolemma voltage into changes in myoplasmic calcium concentrations is the dihydropyridine receptor (DHPR). As a result of mechanical coupling of dihydropyridine receptors to calcium release channels (ryanodine receptors, RYRs), intracellular calcium levels increase stimulating muscle contraction. The working hypothesis is that a decrease in dihydropyridine receptors at the tubular sarcolemma in aged skeletal muscle results in a reduced supply of calcium to contractile proteins. The functional consequence of these intracellular changes is a decrease in contractile force (Figure 1). This hypothesis will be assessed using the following specific aims: 1) To determine the amount of DHPR expression in fast-twitch extensor digitorum longus muscle fiber from young (8 months), middle age (18), and old (28) Fisher 344 Brown Norway F1 Hybrids rats. 2) To assess whether reductions in the sarcoplasmic reticulum calcium release with age are a result of uncoupling of calcium release channels (RYRs) to DHPRs. 3) To correlate the decline in properties of skeletal muscle contraction to alterations in intracellular calcium concentrations.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Biological and Clinical Aging Review Committee (BCA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Renganathan, M; Messi, M L; Delbono, O (1998) Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors. J Biol Chem 273:28845-51
Mayhew, M; Renganathan, M; Delbono, O (1998) Effectiveness of caloric restriction in preventing age-related changes in rat skeletal muscle. Biochem Biophys Res Commun 251:95-9
Renganathan, M; Delbono, O (1998) Caloric restriction prevents age-related decline in skeletal muscle dihydropyridine receptor and ryanodine receptor expression. FEBS Lett 434:346-50
Delbono, O; Renganathan, M; Messi, M L (1997) Regulation of mouse skeletal muscle L-type Ca2+ channel by activation of the insulin-like growth factor-1 receptor. J Neurosci 17:6918-28
Delbono, O; Gopalakrishnan, M; Renganathan, M et al. (1997) Activation of the recombinant human alpha 7 nicotinic acetylcholine receptor significantly raises intracellular free calcium. J Pharmacol Exp Ther 280:428-38
Renganathan, M; Messi, M L; Delbono, O (1997) Dihydropyridine receptor-ryanodine receptor uncoupling in aged skeletal muscle. J Membr Biol 157:247-53
Renganathan, M; Messi, M L; Schwartz, R et al. (1997) Overexpression of hIGF-1 exclusively in skeletal muscle increases the number of dihydropyridine receptors in adult transgenic mice. FEBS Lett 417:13-6
Delbono, O; Renganathan, M; Messi, M L (1997) Excitation-Ca2+ release-contraction coupling in single aged human skeletal muscle fiber. Muscle Nerve Suppl 5:S88-92
Renganathan, M; Sonntag, W E; Delbono, O (1997) L-type Ca2+ channel-insulin-like growth factor-1 receptor signaling impairment in aging rat skeletal muscle. Biochem Biophys Res Commun 235:784-9
Delbono, O; Meissner, G (1996) Sarcoplasmic reticulum Ca2+ release in rat slow- and fast-twitch muscles. J Membr Biol 151:123-30